Project Summary Multiple myeloma is the second most common hematologic malignancy in the US with an estimated prevalence of 6.5 cases per 100,000 adults. Despite marked advancements in the treatment of the disease within the last decade, there are few known prevention strategies available to minimize the risk of unfavorable outcomes. The overarching objectives of the proposed study are 1.) to characterize the relationship of obesity with treatment response and clinical outcome among previously untreated patients with multiple myeloma (MM), and 2.) to examine underlying mechanisms of this relationship. Our central hypothesis is that obesity ? a condition characterized by excess adipose tissue ? will be associated with worse treatment response, increased treatment-related toxicities, and inferior progression-free survival. We also hypothesize that obese patients will present at diagnosis with molecularly distinct tumors compared to non-obese patients, as defined by differences in gene expression patterns. We will leverage data from a clinical trial of 700 MM patients under 65 years of age who were uniformly treated and closely monitored for disease progression. This trial is exceptionally well-positioned to test our study hypotheses because it collected positron emission tomography- computed tomography (PET CT) scans on all patients at baseline which provides a refined measure of obesity based on the distribution of lean body mass and fat mass. Another unique feature of the trial is that the cancer transcriptomes of all patients have already been sequenced ? allowing for a novel molecular comparison of the tumors of MM patients by obesity stats. In addition to testing our main study hypotheses, we will also evaluate whether a PET CT measure of obesity is clinically significantly better than the widely used calculation of body mass index (BMI), in terms of its ability to predict clinical outcomes among MM patients. This is a particularly relevant question in the setting of MM, because PET CT scans are increasingly used in the diagnosis and prognostication of MM patients. Thus, if warranted, the use of PET CT imaging to characterize obesity in MM patients could be implemented in the clinical setting to inform decision-making. The proposed program of research will aid in the identification of high-risk, molecularly distinct subgroups of MM patients that may respond poorly to conventional therapies due to obesity-related factors that are accurately measurable and potentially modifiable. This work is expected to inform the development of new precision treatment strategies for MM patients.